Despite nearly two decades of intensive research, relatively little is known or understood about the pathobiological mechanisms of mammalian infections with Borrelia burgdorferi. The characteristic low density of mammalian infections, estimated to be less than 1 spirochete per gram of tissue or ml of blood, complicate in vivo studies at the cellular and molecular levels. Thus such studies are usually conducted with in vitro model systems, leaving many observations and conclusions lacking direct in vivo confirmation. During recent years RMMB has conducted research into cytopathic interactions between Lyme disease spirochetes and human and murine lymphocytes. In vitro studies demonstrated that B. burgdorferi and lipoproteins including OspA, OspB, and OspC, induce lymphocytic activation and proliferaton (Whitmire & Garon, 1993 & 1994), and that B. burgdorferi targets, invades, and lyses human B and T cells (Dorward, et al, 1997. Such cytopathic interactions occurred during co-incubations containing more than 1 spirochete per lymphocyte, perhaps 5-7 orders of magnitude greater than the ratio expected in vivo. Although B and T cells commonly infiltrate sites of spirochetal colonization in mammals, until recently in vivo interactions between spirochetes and lymphocytes had not been detected or observed.